Capillaries are the smallest and most fragile of the body's blood vessels ranging from normally round 3-4 μm, but some capillaries can be 30-40 μmin diameter. They are responsible for what is known as microcirculation—they create a circulatory network within the organs of the body. Each individual capillary does not work alone, as these vessels form a network in order to carry out their role in the circulatory system. They allow the exchange of nutrients and wastes between the blood and the tissue cells, together with the interstitial fluid. This exchange occurs by passive diffusion and by pinocytosis which means ‘cell drinking’. Pinocytosis is used for proteins, and some lipids. There are three different types found in the human body: 1) continuous, 2) fenestrated, and 3) sinusoidal. The differences in the various types are due to their location in the body as well as their particular function.
I. Continuous
The endothelial cells provide an uninterrupted lining, and they only allow smaller molecules, such as water and ions to pass through their intercellular clefts.
II. Fenestrated
Fenestrated capillaries allow extensive molecular exchange with the blood such as the small intestine, endocrine glands and the kidney. The ‘fenestrations’ are pores that will allow larger molecules though. These types of blood vessels are primarily located in the endocrine glands, intestines, pancreas, and glomeruli of kidney.
III. Sinusoidal
Sinusoidal capillaries are special types of open-pore capillary have larger pores (30-40 μmin diameter) in the endothelium. These types of blood vessels allow red and white blood cells (7.5 μm-25 μm diameter) and various serum proteins to pass aided by a discontinuous basal lamina.
Lymphatics:
Similarly, the lymphatic system is a network of tissues and organs that help rid the body of toxins, waste and other unwanted materials. The primary function of the lymphatic system is to transport lymph, a fluid containing infection-fighting white blood cells, throughout the body. Overall, the lymphatic system is part of the circulatory system comprising a network of lymphatic vessels that carry a clear fluid called lymph directionally towards the heart Lymphatic vessels, located throughout the body, are larger than capillaries.
Biomimetic:
Biomimetic is the study of the structure and function of biological systems as models for the design and engineering of materials and machines. Designs formulated using biologically inspired principles will be used to design and develop a biomimetic tissues (i.e. capillaries, lymphatics), and ultimately human organ structures such as (nephron, glomeruli, alveolus) to simulate the biological functions such as filtering and detoxifying clearing of toxins from blood using non-biological or biological (bioengineered) devices.
Recent technological advances have brought a greater understanding of fundamental properties and processes and it has become possible to attempt to ‘mimic’ or synthesize what nature does naturally. This field, now known as biomimetics, covers many new and emerging topics and offers significant potential in the further development of MEMS, microfluidic devices, and lab-on-a-chip systems. Biomimetic designs can encompass surface treatments that mimic physiological processes or use biological principles to enhance performance through geometric optimization.
One example that could play a significant role in improved flow control through microfluidic devices is mimicking the structure of vascular trees and lymphatics. Biological systems of blood vessels are usually arranged in hierarchical structures and a distinctive feature of this arrangement is their multi-stage division or bifurcation. At each generation, the characteristic dimension of the vascular modules will generally become smaller, both in length and diameter Similar configurations occur in a microfluidic manifold 156 with the inlet channel 158 branching into smaller channels 160 as illustrated schematically in FIG. 8B. It should be noted that this is just one configuration, and these branching can take different forms, topologies and various configurations such as crisscrossing, fractal, curvilinear etc. In addition, the inlet and outlet will have several design including a ledged design to control the distribution hydraulic resistance to be three orders of magnitude lower than the forward flow resistance in the permeation region This means that there will be almost no non-uniformity in the pressure laterally across the permeation region.
Generally, microfluidics is the science of designing, manufacturing, and formulating devices and processes that deal with volumes of fluid on the order of microliters or nanoliters. The microfluidic devices often have dimensions ranging from millimeters down to micrometers. Microfluidic systems have diverse and widespread potential applications. Some examples of systems and processes that might employ this technology include inkjet printers, blood-cell—separation equipment, biochemical assays, chemical synthesis, genetic analysis, drug screening,
and mechanical micro-milling. In many instances, the medical industry has shown keen interest in microfluidics technology.
It is known that microfluidics technology is especially useful for heat and mass transfer applications. For the dialysis of blood, or hemodialysis, the purification of blood external to the body, is a process used to treat renal failure. The chemical composition of blood must be controlled to perform its essential functions of bringing nutrients and oxygen to the cells of the body, and carrying waste materials away from those cells. Dialysis replaces some of the kidney's important functions. However, currently there is no efficient liver dialysis available for clinical use toe able to replace many of the important functions of the liver. Generally, dialysis works on the principles of the diffusion and convection of solutes and ultrafiltration of fluid across a semi-permeable membrane.
Generally, blood contains particles of many different sizes and types, including cells, proteins, dissolved ions, and organic waste products. Some of these particles, including proteins such as hemoglobin and albumin, are essential for the body to function properly. Often in dialysis, blood flows by one side of a semi-permeable membrane, and a dialysate, or special dialysis fluid, flows by the opposite side. Smaller solutes and fluid pass through the membrane, but the membrane blocks the passage of larger substances, such as red blood cells, large proteins This replicates the filtering process that takes place in the kidneys, when the blood enters the kidneys and the larger substances are separated from the smaller ones in the glomerulus.
Schematic diagram of a bifurcating vascular network is illustrated in FIG. 4A.
Those skilled in the art will recognize that branching structures found in mammalian circulatory and respiratory systems, minimizes the amount of biological work required to operate and maintain the system. A relationship between the diameter of the parent branching vessel and the optimum diameters of the daughter vessels was first derived by Murray using the principle of minimum work. This relationship is now known as Murray's law and states that the cube of the diameter of a parent vessel (do) equals the sum of the cubes of the diameters of the daughter vessels i.e. d30=d31+d32 d30=2d31 
Biomimetic design principles could play a significant role is mimicking the structure of vascular trees (i.e. glomerular tuft) to improve the flow through microfluidic channels and manifolds. The vessels found in mammalian systems are usually arranged in hierarchical structures and a distinctive feature of this arrangement is their multi-stage division or bifurcation. At each generation, the characteristic dimension of the vascular modules will generally become smaller, both in length and diameter. Similar configurations often occur in microfluidic manifolds with the inlet channel branching into smaller channels.
A generalized form of Murray's law has been developed that can be applied to the design of microfluidic channels and manifolds found in lab-on-a-chip systems. Murray's law was originally developed for cardiovascular systems composed of multi-diameter circular pipes and the present theory has used this biological principle to design constant-depth artificial vascular systems composed of rectangular or trapezoidal cross-sections. Biomimetic principles can now be applied to microfluidic devices fabricated using conventional batch processing techniques. This novel design approach removes the need to fabricate complex, multi-depth microstructures which would otherwise require difficult multi-exposure and alignment steps.
Murray's law was originally derived from biological considerations and its applicability to microfluidic structures is only just being recognized. It has been shown that by carefully selecting the branching parameter governing each bifurcation; it is possible to introduce a prescribed element of control into the flow behavior. For example, hydrodynamic forces may damage shear-sensitive cells and the ability to predict and control a low-shear environment within the network could benefit cell response studies involving free-flowing or anchored cells.
Now this microfluidic technology to generate microvasculature is not a perfect system. After all, different types of microvasculature act more than just delivering the blood to the tissues and organs. The extensive microvasculature is highly involved in many forms of mass transfer which occurs across many forms of capillaries. However, these special properties will be emulated and achieved using various semipermeable membranes with different chemical, physical characteristics and porosities. Hence, when microfluidic technology is used in combination to generate various forms of tissue and organ microvasculatures, they will emulate many types of microvasculature for various medical devices such as specialized dialysis systems, organ/tissue bio-reactors, bio-artificial organ supports and etc.
Microfluidic Capillaries and Lymphatics Technology (MCAL Technology) and its various biomimetically designed microfluidic-based chipset units/modules/segments.
In one embodiment, the special design of a group of microvascular conduits (capillaries & lymphatics) is as follows: The channels of desired shapes with different aspect ratios (width (W), height (H) and length (L)) and various designs and topologies are fabricated on the microfluidic chip utilizing different inert and biocompatible polymers for microfluidic substrates (PDMS, Photo resin, etc.). In addition, double or multilayered microfluidic chips having either different designs or mirror image of each other will be used to sandwich one or multiple types of interchangeable semipermeable membranes separating different layers. It should be noted and emphasized that a permutation of different microfluidic chips with different microchannel structures, shapes and aspect ratios could be used in combination of one or multiple different semipermeable membranes (synthetic, semisynthetic, biocompatible, porous, flux and diverse molecular weight cut-off permeability). This MCAL Technology—core technology—in fact will allow construction of various biomimetically designed microfluidic-based chipset units that act or emulate functions of different capillaries needed for different applications for improvement of human health.
Ultimately, the double or multilayered combination of the microfluidic chips with different channel designs, aspect ratios and semipermeable membranes with different chemical, physical characteristics and porosity will produce many varieties of biomimetic structures that are modular and scalable that could be connected in parallel and/or in series! The permutation of these chipset units will be used to generate so many different types of artificial organ/tissue microvasculature which ultimately be used for production and manufacturing of various medical devices such as specialized dialysis systems, organ bio-reactors, bio-artificial organ supports and etc. that will be used in fields of medical therapeutics, diagnostics and bio-engineering.
Microfluidics enables small dimensions of individual micro-channels 110a-d, which significantly decreases the lateral distance to diffuse through to the exchange semipermeable membrane. As diffusion time scales with the square of the distance, shrinking the lateral dimension just 10 times speeds up the diffusion by a factor of 100. Faster diffusion means more efficient filtration and higher removal percentage even if all other parameters remain the same.
Microfluidics uses photolithography to build very large and dense networks of micro-channels 110a-d with essentially the same ease as making a single channel. This feature allows for a highly efficient network of parallel small channels to be fabricated at low cost. The network combines the fast diffusion with a large increase of surface-to-volume ratio, as the thin sheet device containing the network has the same contact surface area as the traditional device, while having many times smaller volume. This results in a far more efficient device. Furthermore, the use of a large number of small channels allows for individual channel width to remain small enough to avoid mechanical collapse while the channel height is kept very small to allow for fast lateral diffusion. The result is the binary-tree architecture of micro-channels 110a-d as seen in FIG. 8B
It is also necessary to emphasize that multiple types of microfluidic chip units 102a-d may be used in parallel and/or in series in the present invention. The followings are the list of the various microfluidic chipset units that are based on MCAL technology. It should be emphasized that each layer of the MCAL Technology Chipset unit/segment/module may contain 1. Blood and its components 2. Plasma/Serum and their components 3. Fluids with different compositions including nutrients or other necessary cell/tissue support elements, growth hormone etc. 4. Different components of tissue/organ, combination of cells, stem cells and other components of organs and tissues 5. Oxygen/air 6. Dialysate and replacement fluids 7. Albumin 8. Activated Charcoal 9. Lipids 10. Resin, ion exchange resin.
In designing the various microfluidic chipset modules, the microchannels may take any shape, topology and configurations. Hence, any form of microchannel design could be used including but not limited to straight, crisscrossing, fractal, curvilinear channels or interrupted channels using pillar design and etc. However, pillar design as opposed to having complete channels is more optimal. The pillar design will allow 1000 micro width for each “channel” and provide a larger fill volume for each chipset. The dimensions of these pillars could range between I 0-50 microns however smaller than 20 micron may not release well.
For the purpose of the inflow and outflow design of these various microfluidic chipset modules, a ledged design to control the distribution hydraulic resistance to be three orders of magnitude lower than the forward flow resistance in the permeation region. This means that there will be almost no non-uniformity in the pressure laterally across the permeation region.
In addition, each and every microfluidic chipset unit/segment/module that is manufactured based on the MCAL Technology will have the options of integrated heating and cooling elements and the heatsink if needed and are optional.
The most outer layers on each side of the module are heatsinks. The TEC only pumps heat and for cooling the module down, a heatsink is placed to dissipate energy. To heat up the module, the heatsinks capture the energy.
One microfluidic MCAL Technology module may have any or all the 7 layers:
For the purpose of the inflow and outflow design of these various microfluidic chipset modules, a ledged design to control the distribution hydraulic resistance to be three orders of magnitude lower than the forward flow resistance in the permeation region. This means that there will be almost no non-uniformity in the pressure laterally across the permeation region.
In addition, each and every microfluidic chipset unit/segment/module that is manufactured based on the MCAL Technology will have the options of integrated heating and cooling elements and the heatsink if needed and are optional.
                The heating element is a TEC (Peltier device). The copper plates are utilized to transfer the heat and cold uniformly to the MCAL Module. Utilizing the TEC, the various modules have the capacity to perform at one, elevated temperature, or even generate a temperature gradient across the chipset/membrane to motivate faster permeation, diffusion and convection and etc.        The most outer layers on each side of the module are heatsinks. The TEC only pumps heat and for cooling the module down, a heatsink is placed to dissipate energy. To heat up the module, the heatsinks capture the energy.        One microfluidic MCAL Technology module may have any or all the 7 layers:        1. Heatsink        2. The Cooper layer        3. The TEC (Peltier device)        4. The Microfluidic Chipset Unit        5. The TEC (Peltier device)        6. The Copper Layer        7. Heatsink        Furthermore, in another design, the heating and cooling could be built external to the chipset modules as well. Also a couple or more adjacent modules may share some of the components of heating cooling system.        Another optional feature of these MCAL Modules is the capacity to have micro-vibration assembled on each modules and/or a group of modules to have their own dedicated micro vibration unit.        
This innovative and proprietary MCAL Technology has the following benefits which sets it apart from other. These are the followings:                Emulating different vasculatures (capillaries, lymphatics)        Faster Diffusion & Convection        Higher Efficiency        Higher Surface Area (SA) to Volume (V) Ratio (SAN)        Higher Clearances for Important Uremic Toxins        Scalable/From a Smaller Units/modules to a Larger Ones        Can be connected in Series or Parallel or in Combination        Multilayer with each layer acting either as a lymphatic or different type of capillary        Modular & Adjustable        Variable Angled cross flow/Countercurrent Flow        Variable aspect ratios ranging from 10 um to 2 mm        Can be used in many different applications        
This list includes 18 basic units/modules/segments but is not limited to only these configurations. It should be noted that the microfluidic modules beyond a 2-layered design may have a combination of many of these various semipermeable membranes with wide-ranging chemical, physical characteristics as well as porosities. The Bio-Reactor Module—the BR Module—is just an example of this combination of different membranes in a multilayer module design.
1. The HD Chipset (Hemodialysis Function) in formation of this module, any type of high flux or low flux hemodialysis membranes will be used.
2. The UF Chipset (Ultrafiltration Function) in formation of this any type of ultrafiltration membranes will be used.
3. The PS Chipset (Plasma Separation/plasmapheresis) in formation of this any type of plasmapheresis/plasma separation membranes will be used.
4. The HP Chipset (Hemoperfusion) in formation of this any type of hemoperfusion will be used.
5. The AD Chipset (Albumin Dialysis) in formation of this any type of HMWCO membranes will be used.
6. The D Chipset (Diafiltration) in formation of this any type of CRRT membranes will be used.
7. The HDF Chipset (Hemodiafiltration) in formation of this any types of CRRT membranes will be used.
8. The DR Chipset (Dialysis Regeneration) in formation of this a combination of resin, activated charcoal, zirconium etc. will be used.
9. The O Chipset (Oxygenation) in formation of this any type of ECMO membrane will be used.
10. The HD Chipset (Hemodialysis/High Efficiency) in formation of this any type of high efficiency hemodialysis membranes will be used.
11. The ADR Chipset (Albumin Dialysis and Regeneration) in formation of this combination of any type of HMWCO membranes with a combination of resin, activated charcoal, zirconium etc. will be used.
12. The BR (Bio-Reactor Chipset—Tissue Support using HMWCO Membrane) in formation of this combinations of any type of ECMO membrane with all other semipermeable membranes including HMWCO membranes in a multilayered modules.
13. The RO (the reverse Osmosis) in formation of this any type of reverse osmosis membranes will be used.
14. The FO (Forward Osmosis) in formation of this any type of forward osmosis membrane will be used.
15. The EDI (Electrodeionization) in formation of this any type of ion exchange membranes and resins will be used.
16. The ED (Electrodialysis) in formation of this type of ion-exchange membranes in combination with an applied electric potential difference. Electrodialysis (ED) is used to transport salt ions from one solution through ion-exchange membranes to another solution under the influence of an applied electric potential difference. This is done in a configuration called an electro-dialysis cell.17. The EF (Electrofiltration) in formation of this any type of membrane filtration and electrophoresis process will be used. Electrofiltration is a method that combines membrane filtration and electrophoresis in a dead-end process.18. The LD (Lipid Dialysis) in formation of this any type of membranes to dialyze against any inert and biocompatible lipid solutions will be used.
Each Chipset module is designed to emulate some of the function of human capillaries or lymphatic (though not exactly and precisely). Each basic chipset module which utilizes a specific or various semipermeable membranes to allow manipulation of blood, blood components, plasma, water, electrolytes, nitrogenous waste, amino acids, albumin, globulins, hormones and enzymes, nitrogenous waste, nutrients, and gases.
Different Types of Applications for the Microfluidic-based Capillaries and Lymphatic Technology (MCAL Technology) and its various biomimetically designed microfluidic-based chipset units mentioned above.
#1. Combined microfluidic based kidney and Liver dialysis device for MODS and/or Sepsis
#2. Mobile, modular and scalable kidney and/or liver dialysis systems
#3. Microfluidic based Bio-Reactors for various organ/tissue support systems
#4. Bio-Artificial organ support systems (combinations of #3 with #1 or #2)
#5. Microfluidic based on demand Intravenous Fluid and dialysate Generator: For generating ultrapure water from tap water for intravenous use or dialysate use . . . . This will allow to generate different types of i.v. fluids for medical use.
Combined Microfluidic Based Kidney and Liver Dialysis Device for Liver Failure and Multi-Organ Dysfunction Syndrome (MODS) and/or Sepsis
This is the design for a modular and scalable combined kidney and liver dialysis device that is based on the MCAL Technology. This highly efficient dialysis device will replace the inefficient hollow Fiber Technology currently in clinical use. This device is termed combined microfluidic based kidney and Liver dialysis device using combination of the MCAL Technology core technology building-block units a modular microfluidic dialysis system can be designed which provides a hemodialysis device to perform both kidney and liver dialysis needed in liver failure and also multiorgan failure in MODS and sepsis.
The currently available dialysis devices essentially only eliminate water-soluble substances of low or intermediate molecular weight, hence they are very inefficient.
These standard dialysis based processes do not achieve sufficient removal of uremic toxins (the middle molecules) as well as the notorious protein-bound substances.
In addition, currently, there is no liver dialysis system to provide clearance of tightly bound hepatic toxins accumulated during liver failure.
Therefore, for acute liver failure or an acute exacerbation of chronic liver failure (acute on chronic liver failure) regular dialysis modalities are not sufficient.
However, in this unique combined microfluidic based kidney and Liver dialysis device a combination of the known dialysis processes (diffusive, convective as well as adsorptive, CRRT, Hemodialysis, hemodiafiltration, hemoperfusion, albumin dialysis and novel and unique lipid dialysis)) with “special” maneuvers that manipulate the blood, plasma (utilizing plasma separation/plasmapheresis membranes technology), which will increase the efficiency of standard dialysis plus ultimately increasing the free serum concentration of “protein-bound toxins” could effectively improve the inefficiency of dialysis for kidney or liver as well as Kidney and Liver. Simply put, this is the basis for the combined microfluidic based kidney and Liver dialysis device.
It is important to note that the fashion that these membranes and filters are placed together and their permutation are part of this patent.
The Combined microfluidic-based kidney and Liver dialysis device can be made in a compact form to be used for many different types of Multi-System/Multi-Organ Dysfunctions associated with liver and kidney failure such as:
Acute on Chronic Liver Failure (ACLF)
ALF (Acute Liver Failure)+AKI or CKD
CLF (Chronic Liver Failure)+AKI+CKD
AKI
Sepsis
MODS
Combined microfluidic based kidney and Liver dialysis device utilizes the following mechanisms to increase efficiency of kidney dialysis as well a liver toxin removal:                Reducing Recirculation (use of two accesses, each in a different limb, to decrease recirculation entirely)        Reducing the blood flow and blood volume required for optimal dialysis        Reducing dead-space (After plasmapheresis mostly the plasma is occupying the precious membrane surface area that is so crucial for the more efficient dialysis processes.)        Increasing the convective dialysis by increasing                    a. Ultrafiltration            b. Internal filtration                        Increasing the free serum concentration of the protein-bound toxins via dilution with Specialized Replacement Fluids to favor the equilibrium towards higher serum concentration of the non-bound toxins                    c. Example. 1:4 dilution and subsequently a 1:4 dilution via replacement fluids will yield a 1:16 dilution of the free toxins which will force the change in equilibrium                        Certain chemicals can change the equilibrium as well as the temperature        Use of albumin for albumin dialysis        Use of novel lipid dialysis (optional)        Using combination of Albumin with/without Charcoal and Resins for a specialized albumin based dialysis and specialized dialysate        
This device utilizes a plurality of various microfluidic-based chipset units/modules/segments—based on MCAL Technology—that are arranged in modular configuration for efficient dialysis of blood and dialysate; whereby the microfluidic device comprise of various modules, having integrated micro-pumps for continuous pumping of blood and dialysate, micro-valves for determining flow direction of the blood and dialysate, and a plurality of biomimetically designed micro-channels that emulate the natural microvasculature of the body for optimal flow of blood and dialysate, whereby a microfluidic dialysate regenerating unit/module (DR Module) independently regenerates spent dialysate for use by the microfluidic units (optional).
Those skilled in the art will recognize that the loss of kidney function results in the accumulation of many metabolites, some of which have been identified and their toxic effects on cell metabolism elucidated. These toxins fall under the two categories of 1. Middle molecular weight uremic toxins and 2. Small solutes that are highly protein bound and are difficult to remove from the blood via regular diffusive dialysis. These are the protein-bound uremic toxins Over a hundred of such uremic toxins have been identified, and their removals by various modalities of renal and liver replacement therapy have been studied.
Liver function is regularly divided into two major categories: 1. Synthesis and 2 Toxin removal. The liver synthesizes many of the essential proteins for body function. In addition liver is an active organ in metabolism of many toxins and their removal. The only current therapy to return the hepatic synthetic function is only liver transplantation. Liver transplantations are performed on less than 25% of patients with acute liver failure because no adequate process for taking over the detoxification function exists, so the time taken for the hepatic function to recover cannot be bridged.
Uremic and hepatic toxins are accumulated in a number of diseases related to the kidney and liver diseases respectively. The major difference between the uremic and hepatic toxins is that majority of the hepatic toxins are protein-bound complexes, hence not easily dialyzable. Therefore, for acute liver failure or an acute exacerbation of chronic liver failure (acute on chronic liver failure) regular dialysis modalities are not sufficient.
Hepatic toxins associated with liver failure vary with respect to molecular size and physicochemical characteristics. Typically, a significant proportion of toxins are albumin-bound (e.g. bilirubin, bile acids, and hydrophobic amino and fatty acids). There is growing evidence suggesting an important role of these toxins in the development and maintenance of multi-organ failure subsequent to hepatic failure. Another significant proportion of toxins comprise water-soluble toxins of low- and middle-molecular weight. They are derived either from hepatic failure (e.g. ammonia), or renal dysfunction and are efficiently removed by either hemodialysis or hemofiltration. To date, however, conventional methods failed to remove of albumin-bound toxins effectively.
Other proposals have involved dialysis systems for the liver dialysis which currently is non-existence and for improvement of kidney dialysis adequacy. In addition to limited efficiency, they only provide marginal and partial removal of middle molecular weight toxins Thus, there are great unmet needs exist in the industry to address the aforementioned deficiencies and inadequacies.
The general design of the Combined microfluidic-based kidney and Liver dialysis device is utilizing the MCAL Technology—the various Core Technology microfluidic chipset units/modules in different combinations and permutations. This novel dialysis device will have several different components comprise of the modular and scalable basic microfluidic chipset units/modules that are connected in parallel and/or in series either on or off one or multiple microfluidic chips to design and develop the desired devices. It should be noted that in order to improve the efficiency of this unique microfluidic based dialysis device, the arterial and venous ports are separated and are placed on opposite limbs to decrease the recirculation rate close to zero.
The blood from the patient is pumped through a single lumen catheter (the arterial line of the dialyzer), and then is anticoagulated (if needed) before entering the first module of the combined microfluidic based kidney and Liver dialysis device.
The components of the combined microfluidic-based kidney and Liver dialysis device are as follows:                1. PS module/unit (plasma separation)        2. HD module/unit (Hemodialysis)        3. HP module/unit (Hemoperfusion)        4. HDF or DF module/unit (Hemodiafiltration) or (Diafiltration)        5. AD module (Albumin Dialysis)        6. ADR module (Optional Regeneration of Albumin Dialysate)        7. DR module (Optional Dialysate regeneration)        8. LD module (Optional Lipid Dialysis)Note: The device can either initially performs1. A regular hemodialysis or hemodiafiltration plus replacement fluid on the whole blood and then perform the plasmapheresis to generate plasma portion for further manipulation and dialysis.2. Perform a plasmapheresis generate a plasma portion then perform a regular hemodialysis and/or hemodiafiltration etc. on the plasma portion.The Cellular portion from the plasmapheresis will be returned to patient immediately or go through a regular dialysis additionally (optional).        
The PS Module—This module is designed to emulate some of the function of a glomerulus in human nephron, (though not exactly and precisely). The G module which utilizes the plasmapheresis membrane will allow plasma Water, Albumin, Globulins, Amino acids, Hormones and Enzymes, Nitrogenous waste, Nutrients, Gases and Fibrinogen to be filtered Therefore, the PS module will filter all non-cellular components of the whole blood and generate two portions.
One portion is the portion containing mostly the cellular elements of the blood (WBCs, RBCs and Platelets) and some plasma. This is called Cell Portion (CP).
The other portion is the portion containing non-cellular components of the whole blood (all proteins, electrolytes, and albumin). This is called the plasma portion (PP).
The CP will be directed back to the patient (BTP), while the PP portion enters the next module of the dialysis apparatus to be dialyzed and cleaned.
The HD module—This module is designed to emulate partial clearance of glomerulus and tubules.
The PP will be diluted 1:1 to 1:4 ratios by an isotonic replacement fluid (RF) using a reservoir that contains fresh unused RF. This 1:1 to 1:4 (Plasma: RF) dilutions drastically reduces the albumin and protein concentration of the PP hence increasing the free plasma portion of protein and albumin-bound toxins. In addition the dilution reduces the risk of coagulation and hence the need for anticoagulation.
The HDF Module—This module is designed to emulate the filtration function of the glomerulus in the human nephron. The diluted PP enters the HDF module which utilizes hemodiafiltration membrane and undergoes a good diffusive and convective dialysis in addition to an intensive internal filtration due to increased length of the fiber/channel as well as decreased diameter of the fiber/channel. Of course a dialysate is used during this process which will be regenerated through the DR module. The PP which is well dialyzed is directed to the next module of the dialysis device. (Option/to save dialysate using the back filtration we regenerated some due to reduced filtration).
The HP Module—This module is designed to imitate the function of the tubule portion of human nephron. The well dialyzed PP now enters the HP module which utilizes a hemoperfusion procedure using a suspension of charcoal and resin. PP will be hemoperfused against the fresh resin and charcoal. The PP is further cleared from protein-bound toxins. The PP is again diluted I: to I:4 using fresh isotonic replacement fluid before entering the next module.
The AD Module—This module is designed to imitate another function of the tubule portion of the human nephron. The PP enters the AD module which utilizes a high performance membrane with very High-Molecular-Weight Cut-Off (HMWCO) characteristic to perform an Albumin Dialysis. The PP will be dialyzed against a reservoir of fresh albumin or a combination of albumin plus charcoal/resin. This reservoir will be regenerated to remove the captured protein-bound toxins and avoid saturation of albumin binding. The PP is returned via a separate line using a single lumen catheter to the patient via the opposite limb as explained above.
The DR Module—This module is designed to regenerate the spent dialysate using a reservoir of charcoal and resin. The spent dialysis is run through the suspension of charcoal and resin and other substances to regenerate the dialysate. The regenerated dialysate is returned to the required modules as needed. Option: this regeneration can be eliminated and dialysate fresh can be used without regenerating it.
The ADR module—this module is designed to regenerate the spent albumin.
The MCAL Technology module ADR (Albumin Dialysis Regeneration)
A multilayered PDMS based Microfluidic Chipset for more efficient albumin dialysis
A multilayered PDMS microfluidic chipset is designed for performing much more efficient albumin dialysis and removal of the protein/albumin-bound toxins. This chip design is unique since the albumin regeneration is built on the chip.
A multilayered PDMS based microfluidic chipset. At least a single layer of PDMS for blood compartment (blood layer) sandwiched between two two-layered charcoal and albumin dialysate layers placed in mirror image.
Between each of the following layers, the 1st & 2nd, 2nd & 3rd, 3rd & 4th and 4th & 5th layers, a high flux membrane (or other semipermeable membranes) will be placed to separate each layer compartment and provide the surface for dialysis to occur.
Note: All fluids flow in a countercurrent direction respect to their adjacent layers
The concurrent, countercurrent as well as tangential cross flows may be used for best and optimal efficiency
The membranes used can vary but high flux or even membranes with higher MWCO characteristics may be utilized. In addition, the rate of flow for each layer will be studied and optimized.
The diluted and well dialyzed PP enters this module—the A module which emulates the function of the tubule portion of the human nephron. The diluted PP enters the A module where Albumin dialysis is performed using High-Molecular-Weight Cut-off (HMWCO) membrane/High Performance Membrane which allows the PP to be dialyzed against albumin or a combination of albumin plus charcoal/resin. The first output of the MCAL Technology—the PP portion—will be directed back to the patient/subject while the second output of this module—the spent albumin dialysate—will be directed to the module DR for regeneration.
The RO Module—This module is designed to emulate the function of the collecting tubule portion of the human nephron. The spent dialysate plus ultrafiltration will enter the RO module which utilizes a reverse osmosis membrane to extract the water and the rest is discarded as urine like material. The water is then used for other functions in the device.
The present invention is directed to a modular and scalable microfluidic unit that each that utilizes different and various principles of microfluidics for performing different processes on blood and plasma. These processes includes but not limited to filtration, ultrafiltration, diafiltration, various forms of dialysis, hemoperfusion, plasma separation and etc. of any fluid, such as blood, plasma and lymph. The modular microfluidic dialysis system provides a portable, wearable hemodialysis device that helps remove middle molecular weight uremic toxins, small solutes, hepatic toxins, water, and other impurities from the blood through the use of microfluidic technology. The microfluidic dialysis system provides particular advantages in blood dialysis for mobile kidney augmentation devices, liver treatment, and fabrication of an artificial kidney.
In one embodiment, the system utilizes various micro-components that emulate the physiological parameters of the body. These micro-components provide numerous advantageous over traditional dialysis, such as hollow tube filtration and reverse osmosis. In this manner, the middle molecular weight uremic toxins and small solutes may be filtered out of the blood more efficiently. Furthermore, the system is modular, so as to enable scalability and conformance to different body types and requirements.
In some embodiments, the system may utilize a portable, lightweight, and wearable hemodialysis device. The device is battery operated. The device utilizes tubing to connect to the patient and to a disposable cassette that contains the means for processing the blood and dialysate. A simple user interface enables operation of the device and monitoring of blood temperature and pressure. A data transmission portion, such as a Wi-Fi transmitter, enables real time monitoring of physiological parameters of the body and mechanical parameters of the system.
In one aspect, a modular microfluidic dialysis system, comprises:                a plurality of microfluidic units, the plurality of microfluidic units configured to enable any one of different forms of blood filtration, ultrafiltration, diafiltration, plasma separation and dialysis of blood, the plurality of microfluidic basic building block units can be arranged in modular configuration in parallel or in series for enabling scalability, the plurality of microfluidic units at least partially fabricated from inert and biocompatible polymers commonly used in microfluidic such as a polymeric organosilicon compound, the plurality of microfluidic units comprising:                    a blood microfluidic chip and a dialysate microfluidic chip, the blood microfluidic chip configured to carry blood, the dialysate microfluidic chip configured to carry a dialysate,            the blood microfluidic chip and the dialysate microfluidic chip comprising a plurality of micro-pumps, the plurality of micro-pumps configured to pump the blood to and from the blood microfluidic chip, the plurality of micro-pumps further configured to pump the dialysate to and from the dialysate microfluidic chip,            the blood microfluidic chip and the dialysate microfluidic chip further comprising a plurality of micro-valves, the plurality of micro-valves configured to regulate the flow of the blood and the dialysate,                        the blood microfluidic chip and the dialysate microfluidic chip further comprising        a plurality of micro-channels, the plurality of micro-channels configured to carry the blood to and from the blood microfluidic chip, the plurality of micro-channels further configured to carry the dialysate to and from the dialysate microfluidic chip, the plurality of micro-channels defined by multiple widths and topographies; and        a semipermeable membrane, the semipermeable membrane disposed between the blood microfluidic chip and the dialysate microfluidic chip, the semipermeable membrane configured to form a permeable barrier between the blood and the dialysate, the semipermeable membrane further configured to enable passage of toxins and water from the blood in the blood microfluidic chip to the dialysate in the dialysate microfluidic chip; and                    a microfluidic regenerating unit, the microfluidic regenerating unit configured to at least partially filter contaminated dialysate received from the dialysate microfluidic chip, the microfluidic regenerating unit further configured to return regenerated dialysate to the dialysate microfluidic chip.                        
In a second aspect, the polymeric organosilicon compound is PDMS.
In another aspect, the plurality of micro-pumps comprises electric micro-pumps and pneumatic micro-pumps.
In another aspect, the plurality of micro-pumps comprises two blood micro-pumps, a heparin micro-pump, an ultrafiltration micro-pump, and a dialysate micro-pump.
In yet another aspect, the plurality of micro-channels have a wide inlet, a narrow median region, and a narrow outlet.
In yet another aspect, the plurality of micro-channels has a wide inlet, a narrow median region, and a wide outlet or a combination of these characteristics.
In yet another aspect, the plurality of micro-channels is configured in substantially the same or different topography and width as a microvasculature of thebody.
In yet another aspect, the plurality of micro-channels have a wide raging width of about I00-2000 microns, a depth of about between IO to I00 microns, and a length of about between I to 20 centimeters.
In yet another aspect, the topography of the plurality of micro-channels includes at least one member selected from the group consisting of: straight, parallel, crisscross, fractal pattern, loops, and branched.
In yet another aspect, the dialysate is an ultrapure dialysate
In yet another aspect, the microfluidic regenerating unit includes at least one member selected from the group consisting of: a sediment filter, a carbon filter, a zirconium carbonate filter, a deionizing resin, a micro-filter, an ultraviolet light, 0.22 micron filter, and a cold plasma regeneration apparatus.
In yet another aspect, the microfluidic regenerating unit is configured to regenerate between 300 milliliters to 1500 milliliters of dialysate.
In yet another aspect, the microfluidic dialysis regenerating unit comprises a slot, the slot configured to receive a vial of the dialysate.
In yet another aspect, the microfluidic regenerating unit comprises dimensions of about 20 centimeters in length by 10 centimeters in width by 10 centimeters in height.
In yet another aspect, the system further comprises one or several warming devices, the warming device configured to activate charcoal and other optional sections.
In yet another aspect, the system further comprises one or more cooling devices.
In yet another aspect, the system further comprises a data transmission portion, the data transmission portion configured to enable real time monitoring of physiological parameters of the body and mechanical parameters of the system.
In yet another aspect, the data transmission portion comprises a Wi-Fi transmitter.
In yet another aspect, the modular configuration of the system is configured such that about I 0-100 microfluidic units form a microfluidic construct.
In yet another aspect, the modular configuration of the system is configured such that about 5-20 microfluidic constructs form a microfluidic module.
In yet another aspect, the microfluidic module positions inside microfluidic housing
In yet another aspect, the plurality of micro-valves are configured to close if the microfluidic module is not disposed in an operable orientation inside themicrofluidic housing.
In one embodiment, the device comprises a plurality of microfluidic units that receive, filter, and return the blood and dialysate to the body and dialysate reservoir, respectively. The microfluidic units are arranged in modular configuration for enhanced scalability, such that the microfluidic units can be added, removed, or rearranged to conform to the dialysis needs of the patient. This allows for more efficient dialysis of the blood.
The multilayered microfluidic units comprise one or multiple blood microfluidic chips, two or more dialysate microfluidic chips, and one or more semipermeable membranes having different characteristics disposed between the chips. The two or more chips (membranes, filters, etc) have substantially the same configuration, i.e., mirror images of each other, though various configurations can be used as needed. In one embodiment, all the blood microfluidic chips and all the dialysate microfluidic chips comprise integrated micro-pumps for pumping blood and dialysate continuously. This minimizes the need for excessive quantities of dialysate. The chips further comprise micro-valves for determining flow direction. The micro-valves remain closed if the chips are not properly aligned.
The chips further comprise a plurality of micro-channels for carrying the blood and dialysate to the appropriate chip. The micro-channels are configured to emulate the natural microvasculature of the body, i.e., capillaries, arterioles, venules and lymphatics. In one embodiment, the micro-channels include a narrow channel having different topologies and widths for optimal flow of blood and dialysate. This unique configuration of the micro-channels creates fluid shear rates that are amenable to red blood cells contained in blood. The micro-channels have substantially smaller diameters than the current hollow fiber technology; thereby enabling more efficient diffusive and convective fluid flow.
The micro-pumps, micro-valves, and micro-channels are fabricated directly on the respective chip. The micro-pumps, micro-valves, and micro-channels are also fabricated from inert and biocompatible polymers like a polymeric organosilicon compound, such as PolyDiMethylSiloxane (PDMS). Those skilled in the art will recognize that PDMS provides numerous advantageous for microfluidics, including: unique rheological properties for enhanced blood and dialysate flow, transparency for viewing the blood and dialysate, deformability for forming desired micro-channel configurations, sticking properties for adhering to other PDMS components, and non-toxicity.
The blood microfluidic chip and the dialysate microfluidic chip sandwich a semipermeable membrane that provides the filtering capacity for the dialysis. The semipermeable membrane is configured to form a permeable barrier between the blood and the dialysate. In this manner, the semipermeable membrane enables passage of toxins, water, and small electrolytes from the blood in the blood microfluidic chip to the dialysate in the dialysate microfluidic chip. In one embodiment, the semipermeable membrane allows only water and small electrolytes to pass.
The device further includes a microfluidic dialysis regenerating unit that independently regenerates spent dialysate for use by the dialysate microfluidic chip. By regenerating the dialysate, a minimal amount of dialysate is required for operation of the device. In one exemplary use, the microfluidic regenerating unit is configured to regenerate between 300 milliliters to 1500 milliliters of the dialysate.
The microfluidic dialysis regenerating unit utilizes various sediment filters, carbon filters, deionizing resin, micro-filters, and optional ultraviolet lights and/or cold plasma technology for sterilization and 0.22-micron filter to generate an ultrapure dialysate regeneration unit (Optional). The microfluidic dialysis regenerating unit negates the need for reverse osmosis filtering techniques. The microfluidic dialysis regenerating unit further comprises a slot for receiving a vial of dialysate. In one embodiment, a plurality of microfluidic dialysis regenerating units fit into a regenerating unit housing.
In some embodiments, the system is modular to enable scalability, adjustability and adaptability for accommodating different types of patients with various sizes, accumulated toxin types in the blood (hepatic vs. uremic toxins), medical conditions, support requirement and dialysate requirements. The two or multilayered blood microfluidic chip(s), the dialysate microfluidic chip(s), and the semipermeable membrane(s) sandwiched there between forms various microfluidic units. About I0-100 microfluidic units form a microfluidic construct. About 5-20 microfluidic constructs form a microfluidic module. The microfluidic module positions inside a microfluidic housing. In one embodiment, the microfluidic module must be aligned properly inside the microfluidic housing before the micro-valves open.
One objective of the present invention is to utilize MCAL technology basic building blocks and micro-channels having microvasculature characteristics for performing dialysis.
Another objective is to provide a hemodialysis device that is portable, wearable, light-weight and easy to use, and patient friendly.
Another objective is to provide a microfluidic-based dialysis system that removes middle molecular weight uremic toxins, small solutes and/or protein-bound toxins.
Another objective is to regulate extracellular fluid volume and blood pressure control, electrolyte, acid base control, and correction of anemia.
Yet another objective is to fabricate the micro-channels from a polymeric organosilicon compound, such as PDMS, that has unique rheological properties that enhance flow of blood and dialysate, is transparent, sticks to other micro-channels and the respective chip, is deformable, and nontoxic.
Yet another objective is to create a scalable configuration that enables adding, removing, and rearranging microfluidic modules from the microfluidic housing.
Yet another objective is to provide a microfluidic regenerating unit to replace reverse osmosis functions and components.
Yet another objective is to incorporate the microfluidic housing and the regenerating unit housing in a disposable cassette.
Yet another objective is to enable real time monitoring of the physiological aspects of the blood and body parts, and the mechanical components of the system.
Yet another objective is to provide a dialysis system that can operate continuously or intermittently, operating from 2-24 hours/day seven days a week.
Yet another objective is to enable gentle ultrafiltration to avoid severe post-dialysis fatigue and fluid shifts seen by regular dialysis methods.
Yet another objective is to regenerate dialysate fluid to minimize the amount of dialysate used daily to as little as 300 ml/day to 1500 ml/day.
Yet another objective is to provide cost effective dialysis for treatment of liver and/or kidney failures.
Other systems, devices, methods, features, and advantages will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims and drawings.
Like reference numerals refer to like parts throughout the various views of the drawings.